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Proton Pump Inhibitors Act With Unprecedented Potencies as Inhibitors of the Acetylcholine Biosynthesizing enzyme-A Plausible Missing Link for Their Association With Incidence of Dementia

Kumar R, Kumar A, Nordberg A, Långström B, Darreh-Shori T  (2020) Alzheimers Dement.   May 8. doi: 10.1002/alz.12113. Online ahead of print. 

Web URL: Read this and related abstracts via PubMed here

Abstract:

Introduction: Several pharmacoepidemiological studies indicate that proton pump inhibitors (PPIs) significantly increase the risk of dementia. Yet, the underlying mechanism is not known. Here, we report the discovery of an unprecedented mode of action of PPIs that explains how PPIs may increase the risk of dementia.

Methods: Advanced in silico docking analyses and detailed enzymological assessments were performed on PPIs against the core-cholinergic enzyme, choline-acetyltransferase (ChAT), responsible for biosynthesis of acetylcholine (ACh).

Results: This report shows compelling evidence that PPIs act as inhibitors of ChAT, with high selectivity and unprecedented potencies that lie far below their in vivo plasma and brain concentrations.

Discussion: Given that accumulating evidence points at cholinergic dysfunction as a driving force of major dementia disorders, our findings mechanistically explain how prolonged use of PPIs may increase incidence of dementia. This call for restrictions for prolonged use of PPIs in elderly, and in patients with dementia or amyotrophic lateral sclerosis.

Keywords: Alzheimer's disease; Down's syndrome; Lewy body dementia; acetylcholine; amyotrophic lateral sclerosis; choline-acetyltransferase; cholinergic system; dementia; esomeprazole; in silico analyses; lansoprazole; omeprazole; pantoprazole; proton pump inhibitors; rabeprazole; tenatoprazole.

FAB RESEARCH COMMENT:

See the associated news article, and FAB comments on the implications of this research - which are potentially important at the personal, professional and public health level.


This research shows that Proton Pump Inhibitors (PPIs) can strongly suppress the synthesis of acetylcholine - a key neurotransmitter involved in movement and cognitive function.

These findings offer a new and highly plausible mechanism to explain the established link between long-term use of PPIs and increased risks for dementia.

However, other mechanisms by which chronic use of these medications could increase risks for cognitive decline, dementia and other mental health problems have already been documented. 

For example, PPIs (and other antacids) can increase risks for Vitamin B12 deficiency - and this nutrient is critical for healthy brain and nerve function. See:


Depletion of iron levels is yet another potential negative side-effect of PPIs, according to large-scale population studies.  Even sub-cinical iron deficiency, let alone overt anaemia, is associated with impaired cognition, as well as fatigue and mood as well as physical health problems. See: